Polly E. Parsons

Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma.

Animal studies implicate gut bacterial translocation via the portal vein as a major factor in the pathogenesis of postinjury multiple organ failure (MOF). We therefore inserted portal vein catheters for sequential blood sampling in the operating room, at 6, 12, 24, and 48 hours, and 5 days postoperatively in 20 injured patients (13 blunt, seven penetrating; mean age, 34 years) requiring emergent laparotomy and who were at known risk for MOF. The mean Revised Trauma Score was 6.4 +/- 0.4, and the Injury Severity Score, 29.3 +/- 2.3. Twelve (60%) patients arrived in shock (SBP less than 90 torr). Eight (2%) of 212 portal blood cultures were positive; seven were presumed contaminants. The only positive systemic culture (total, 212) was a Staphylococcus aureus on day 5 in a patient with a concurrent staphyloccal pneumonia. In the first 48 hours, we could not detect endotoxin in portal or systemic blood. Additionally, simultaneous portal and systemic blood levels of complement fragment C3a, tumor necrosis factor, and interleukin-6 were nearly identical and, specifically, were not different in those patients who developed MOF. In summary, this prospective clinical study has not confirmed portal or systemic bacteremia within the first 5 days postinjury, despite an eventual 30% incidence of MOF.

Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: time for a reevaluation.

&NA; Definitions for sepsis, septic shock, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) were developed by consensus conferences with the goal of achieving standardization of terminology and improved homogeneity of patient populations in clinical studies. Although such definitions have been useful in epidemiologic investigations, the criteria specified by the consensus conferences are broad and insufficiently specific to address the problem of heterogeneous mechanisms leading to clinical syndromes. An important challenge is to progress from clinical syndromes, as presently defined, to more specific entities that are delineated by alterations in specific immunologic or biochemical pathways. Such mechanistic definitions will provide more homogeneous groups of patients who can be identified at early stages of their clinical course. This approach encourages focused investigation of pathways leading to organ system dysfunction and death and, also, provides an efficient framework for the development of new therapies useful in critically ill patients.

Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury

Objectives: To determine whether baseline plasma levels of the receptor for advanced glycation end products (RAGE), a novel marker of alveolar type I cell injury, are associated with the severity and outcomes of acute lung injury, and whether plasma RAGE levels are affected by lower tidal volume ventilation. Design, setting and participants: Measurement of plasma RAGE levels from 676 subjects enrolled in a large randomised controlled trial of lower tidal volume ventilation in acute lung injury. Measurements and main results: Higher baseline plasma RAGE was associated with increased severity of lung injury. In addition, higher baseline RAGE was associated with increased mortality (OR for death 1.38 (95% CI 1.13 to 1.68) per 1 log increment in RAGE; p = 0.002) and fewer ventilator free and organ failure free days in patients randomised to higher tidal volumes. These associations persisted in multivariable models that adjusted for age, gender, severity of illness and the presence of sepsis or trauma. Plasma RAGE was not associated with outcomes in the lower tidal volume group (p = 0.09 for interaction in unadjusted analysis). In both tidal volume groups, plasma RAGE levels declined over the first 3 days; however, the decline was 15% greater in the lower tidal volume group (p = 0.02; 95% CI 2.4% to 25.0%). Conclusions: Baseline plasma RAGE levels are strongly associated with clinical outcomes in patients with acute lung injury ventilated with higher tidal volumes. Lower tidal volume ventilation may be beneficial in part by decreasing injury to the alveolar epithelium.

Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock.

ObjectiveAlcohol is one of the most commonly used drugs in the world and causes dysfunction in many vital organs. However, the effects of chronic alcohol abuse on acute lung injury and nonpulmonary organ dysfunction are relatively unexplored. The goal of this study was to determine the effects of chronic alcohol abuse on the incidence and severity of the acute respiratory distress syndrome and multiple organ dysfunction syndrome in patients with septic shock. DesignMulticenter prospective epidemiologic study. SettingIntensive care units of four university urban hospitals. PatientsA total of 220 critically ill patients with septic shock. Measurements and Main FindingsThirty percent of the patients (66 of 220) were identified as having a history of chronic alcohol abuse based on a positive response to an alcohol screening questionnaire. The incidence of acute respiratory distress syndrome in patients with a positive history of chronic alcohol abuse was 70% (46 of 66), compared with 31% (47 of 154) in individuals without a history of chronic alcohol abuse (p < .001). After adjusting for differences in the source of infection, sex, age, chronic hepatic dysfunction, diabetes, severity of illness, nutritional status, and smoking status, the effects of chronic alcohol abuse on the incidence of acute respiratory distress syndrome remained significant (p < .001; odds ratio, 3.70; 95% confidence interval, 1.83–7.71). The effect of the source of infection (pulmonary vs. nonpulmonary) on the development of acute respiratory distress syndrome also remained significant in this multivariable analysis (p < .001; odds ratio, 3.68; 95% confidence interval, 1.95–7.18). Based on the highest daily Sequential Organ Failure Assessment score, patients with a history of chronic alcohol abuse had more severe nonpulmonary organ dysfunction when compared with nonalcoholics (9.42 ± 3.89 vs. 8.05 ± 4.10, p = .01). After adjusting for source of infection, sex, age, nutritional status, history of diabetes, and smoking status, the effects of chronic alcohol abuse on the incidence of nonpulmonary organ dysfunction also remained significant (p = .03; odds ratio, 2.07; 95% confidence interval, 1.09–3.97). ConclusionsWe conclude that chronic alcohol abuse is an independent risk factor for acute respiratory distress syndrome and increases the severity of nonpulmonary organ dysfunction in patients with septic shock.

Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury

Background: Because injury to the alveolar epithelial barrier is a characteristic feature of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), plasma surfactant protein levels may have prognostic value. To test this hypothesis plasma surfactant proteins A and D (SP-A and SP-D) levels were measured in patients with ALI or ARDS enrolled in the NHLBI sponsored multicentre ARDS Network randomised controlled trial of a 6 ml/kg v 12 ml/kg tidal volume strategy. Methods: Data from 565 participants in the clinical trial were used. Plasma levels of SP-A and SP-D were measured at baseline and on day 3 after the start of the mechanical ventilation protocol. The longitudinal impact of baseline plasma surfactant protein levels on clinical outcomes was examined by multivariate analysis, controlling for mechanical ventilation group, APACHE III score, and other clinical covariates. The effect of 6 ml/kg tidal volume ventilation on plasma SP-A and SP-D levels was evaluated using analysis of covariance. Results: Baseline plasma SP-A levels were not related to any clinical outcome. In contrast, higher baseline plasma SP-D levels were associated with a greater risk of death (OR 1.21 per 100 ng/ml increment; 95% CI 1.08 to 1.35), fewer ventilator-free days (mean decrease −0.88 days; p=0.001), and fewer organ failure-free days (mean decrease −1.06 days; p<0.0001). The 6 ml/kg tidal volume strategy had no effect on the rise in plasma SP-A levels (p=0.91) but attenuated the rise in plasma SP-D levels (p=0.0006). Conclusions: Early in the course of ALI/ARDS an increased level of plasma SP-D is associated with a worse clinical outcome. The 6 ml/kg tidal volume strategy attenuated the rise of SP-D early in the clinical course. Taken together, these observations indicate that plasma SP-D, a product of alveolar type II cells, is a valuable biomarker in ALI/ARDS.

Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials

BACKGROUND Subphenotypes have been identified within heterogeneous diseases such as asthma and breast cancer, with important therapeutic implications. We assessed whether subphenotypes exist within acute respiratory distress syndrome (ARDS), another heterogeneous disorder. METHODS We used data from two ARDS randomised controlled trials (ARMA trial and ALVEOLI trial), sponsored by the National Heart, Lung, and Blood Institute. We applied latent class modelling to identify subphenotypes using clinical and biological data. We modelled data from both studies independently. We then tested the association of subphenotypes with clinical outcomes in both cohorts and with the response to positive end-expiratory pressure (PEEP) in the ALVEOLI cohort. FINDINGS We analysed data for 1022 patients: 473 in the ARMA cohort and 549 in the ALVEOLI cohort. Independent latent class models indicated that a two-class (ie, two subphenotype) model was the best fit for both cohorts. In both cohorts, we identified a hyperinflammatory subphenotype (phenotype 2) that was characterised by higher plasma concentrations of inflammatory biomarkers, a higher prevalence of vasopressor use, lower serum bicarbonate concentrations, and a higher prevalence of sepsis than phenotype 1. Participants in phenotype 2 had higher mortality and fewer ventilator-free days and organ failure-free days in both cohorts than did those in phenotype 1 (p<0·007 for all). In the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on mortality, ventilator-free days and organ failure-free days differed by phenotype (p=0·049 for mortality, p=0·018 for ventilator-free days, p=0·003 for organ-failure-free days). INTERPRETATION We have identified two subphenotypes within ARDS, one of which is categorised by more severe inflammation, shock, and metabolic acidosis and by worse clinical outcomes. Response to treatment in a randomised trial of PEEP strategies differed on the basis of subphenotype. Identification of ARDS subphenotypes might be useful in selecting patients for future clinical trials. FUNDING National Institutes of Health.

Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome

Objective To determine whether the administration of lisofylline (1-[5R-hydroxyhexyl]-3,7-dimethylxanthine) would decrease mortality in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Design A prospective, randomized, double-blind, placebo-controlled, multicenter study. Setting Intensive care units at 21 hospitals at the ten centers constituting the ARDS Clinical Trials Network. Patients A total of 235 patients who met eligibility criteria were enrolled in the study (116 into the lisofylline group, 119 into the placebo group). Interventions Patients were randomized to receive either lisofylline or placebo. The dose of lisofylline was 3 mg/kg with a maximum dose of 300 mg intravenously every 6 hrs. The intravenous solution of study drug was administered over 10 mins every 6 hrs. Dosing was continued for 20 days or until the patient achieved 48 hrs of unassisted breathing. Measurements and Main Results The trial was stopped by the Data Safety Monitoring Board for futility at the first scheduled interim analysis. The patient groups had similar characteristics at enrollment. No significant safety concerns were associated with lisofylline therapy. There was no significant difference between groups in the number of patients who had died at 28 days (31.9% lisofylline vs. 24.7% placebo, p = .215). There was no significant difference between the lisofylline and placebo groups in terms of resolution of organ failures, ventilator-free days, infection-related deaths, or development of serious infection during the 28-day study period. The median number of organ failure–free days for the five nonpulmonary organ failures examined (cardiovascular, central nervous system, coagulation, hepatic, and renal) was not different between the lisofylline and placebo groups. Although lisofylline has been reported to decrease circulating free fatty acid levels, we did not find any such treatment effect compared with placebo. Conclusions In this study, there was no evidence that lisofylline had beneficial effects in the treatment of established ALI/ARDS.

Diabetic patients have a decreased incidence of acute respiratory distress syndrome

Objective Our ability to predict which critically ill patients will develop acute respiratory distress syndrome (ARDS) is imprecise. Based on the effects of diabetes mellitus on the inflammatory cascade, we hypothesized that a history of diabetes might alter the incidence of ARDS. Design A prospective multicenter study. Setting Intensive care units at four university medical centers. Patients One hundred thirteen consecutive patients with septic shock. Interventions None. Measurements and Main Results All patients were prospectively followed during their intensive care course for the development of ARDS. A history of diabetes was identified in 28% (32/113) of the patients. In this study, nondiabetics were more likely to develop septic shock from a pulmonary source (48%, 39/81) compared with diabetics (25%, 8/32) (p = .02). Forty-one percent (46/113) of the patients with septic shock developed ARDS. Forty-seven percent of the nondiabetic patients developed ARDS compared with only 25% of those with diabetes (p = .03, relative risk = 0.53, 95% confidence interval = 0.28–0.98). In a multivariate logistic regression analysis, when we adjusted for several variables including source of infection, the effect of diabetes on the incidence of ARDS remained significant (p = .03, odds ratio = 0.33, 95% confidence interval = 0.12–0.90). Conclusions In patients with septic shock, a history of diabetes is associated with a lower risk of developing ARDS compared with nondiabetics.

Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury

Objective: To identify biological and clinical predictors of acute kidney injury in subjects with acute lung injury. Design: Secondary data analysis from a multicenter, randomized clinical trial. Setting: Intensive care units in ten university medical centers. Patients: A total of 876 patients enrolled in the first National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial. Interventions: Study subjects were randomized to receive a low tidal volume ventilation strategy and pharmacologic therapy with ketoconazole or lisofylline in a factorial design. Measurements and Main Results: We tested the association of baseline levels of interleukin‐6, interleukin‐8, interleukin‐10, von Willebrand factor, tumor necrosis factor‐[alpha], type I and II soluble tumor necrosis factor receptors (sTNFR‐I and ‐II), protein C, plasminogen activator inhibitor‐1 (PAI‐1), surfactant protein‐A, surfactant protein‐D, and intracellular adhesion molecule‐1 with subsequent acute kidney injury. Of 876 study participants who did not have end‐stage renal disease, 209 (24%) developed acute kidney injury, defined as a rise in serum creatinine of >50% from baseline over the first four study days. The 180‐day mortality rate for subjects with acute kidney injury was 58%, compared with 28% in those without acute kidney injury (p < .001). Interleukin‐6, sTNFR‐I, sTNFR‐II, and PAI‐1 levels were independently associated with acute kidney injury after adjustment for demographics, interventions, and severity of illness. A combination of clinical and biological predictors had the best area under the receiver operating characteristic curve, and the contribution of sTNFR‐I and PAI‐1 to this model was highly significant (p = .0003). Conclusions: Elevations in PAI‐1, interleukin‐6, and the sTNFRs in subjects with acute kidney injury suggest that disordered coagulation, inflammation, and neutrophil–endothelial interactions play important roles in the pathogenesis of acute kidney injury. The combination of these biological and clinical risk factors may have important and additive value in predictive models for acute kidney injury.

A Phase II Randomized Placebo-Controlled Trial of Omega-3 Fatty Acids for the Treatment of Acute Lung Injury

Objectives:Administration of eicosapentaenoic acid and docosahexanoic acid, omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury when studied in a commercial enteral formula. However, fish oil has not been tested independently in acute lung injury. We therefore sought to determine whether enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with acute lung injury. Design:Phase II randomized controlled trial. Setting:Five North American medical centers. Patients:Mechanically ventilated patients with acute lung injury ≥18 yrs of age. Interventions:Subjects were randomized to receive enteral fish oil (9.75 g eicosapentaenoic acid and 6.75 g docosahexanoic acid daily) or saline placebo for up to 14 days. Measurements and Main Results:Bronchoalveolar lavage fluid and blood were collected at baseline (day 0), day 4 ± 1, and day 8 ± 1. The primary end point was bronchoalveolar lavage fluid interleukin-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum eicosapentaenoic acid concentration (p < .0001). However, there was no significant difference in the change in bronchoalveolar lavage fluid interleukin-8 from baseline to day 4 (p = .37) or day 8 (p = .55) between treatment arms. There were no appreciable improvements in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil group compared with the control group. Similarly, organ failure score, ventilator-free days, intensive care unit-free days, and 60-day mortality did not differ between the groups. Conclusions:Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof-of-concept studies evaluating new treatments for acute lung injury.